Treatment for basal cell carcinoma

ABSTRACT

The present invention provides a method of treating basal cell carcinoma in a subject. Generally, the method includes administering to the subject an amount of IRM compound effective for treating basal cell carcinoma in a treatment cycle that includes at least two consecutive days in which the IRM compound is administered and at least one day in which the IRM compound is not administered.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/808,004, filedMar. 24, 2004, which claims priority to U.S. Provisional ApplicationSer. No. 60/457,265, filed Mar. 25, 2003.

BACKGROUND

Basal cell carcinoma (BCC) is the most common form of skin cancer andthe most common form of cancer of any type in the United States. Itdevelops in the basal germinative cell layer of the epidermis, often onsun-exposed areas of the skin. Although BCC rarely spreads (i.e.,metastasizes) to other parts of the body, it can be very destructive anddisfiguring. BCC may cause local tissue destruction that may lead todisfigurement or functional impairment of surrounding non-canceroustissue. Disfigurement may be a particular concern of BCC patientsbecause many BCC tumors occur on the sun-exposed—and, therefore, alsotypically otherwise exposed—skin of the head and neck. Larger tumors,tumors that have been present for long periods of time, and tumors thathave recurred after initial therapy may be biologically more aggressiveand especially difficult to cure. While the mortality rate of BCC isrelatively low, its increasing incidence and prolonged morbidity meansthat the disease can be very costly to treat.

A wide variety of surgical and non-surgical therapies are available forBCC. Nonsurgical therapies include radiation therapy, chemotherapy, andimmunotherapy. These therapies can be useful for definitive treatment ofprimary tumors and some recurrent BCC tumors and for relieving symptomsassociated with inoperable tumors. However, some of these therapies alsocan have significant unpleasant side effects. Side effects of radiationtherapy and certain chemotherapies are well documented. One form ofimmunotherapy involves intralesional injections of interferon. Whileinterferon therapy can be effective against BCC, the multipleintralesional injections can require several clinic visits per week formany weeks. Also, many patients can be anxious or otherwiseuncomfortable receiving injections. Thus, interferon therapy can resultin significant patient inconvenience and discomfort.

Interferon therapy also is connected with several side effects such as,for example, flu-like symptoms such as fever, chills, aches, drowsinessand nausea; a reduction in the number of white blood cells; a reductionin the number of red blood cells (anemia); a reduction in the number ofplatelets in the blood, which may give rise to nosebleeds, for example;thinning hair; liver problems; and heart problems.

Surgical therapies include excision, curettage and electrosurgery,cryosurgery, Mohs micrographic surgery, and laser surgery. Excision isuseful for both primary and recurrent tumors and has the advantage ofallowing for histological assessment of surgical margins. Curettage andelectrosurgery involves alternately removing soft tumor tissue with acurette and then destroying an extra margin of tissue byelectrodesiccation, electrocautery, or electrocoagulation. The proceduremay be repeated as necessary. Cryosurgery involves freezing the tumor toa temperature that kills the cells of the tumor. The dead tumor cellscan be removed by, for example, curettage. Mohs micrographic surgery(MMS) involves a surgeon using a microscope to improve identify themargin of the tumor more accurately and more precisely than is possibleby unaided visual inspection. MMS can increase the likelihood that theentire tumor is removed and minimize the amount of normal tissue that isremoved. Laser surgery involves using a laser to vaporize tumor cells.Alternatively, the laser may be used in lieu of a scalpel blade forexcisional surgery.

SUMMARY

It has been found that immune response modifier (“IRM”) compounds canprovide effective therapeutic treatment for BCC. Accordingly, thepresent invention provides a method of treating basal cell carcinoma ina subject. Generally, the method includes administering to the subjectan amount of an IRM compound effective for treating basal cellcarcinoma, wherein the IRM compound is administered in a treatment cyclethat includes at least two consecutive days in which the IRM compound isadministered and at least one day in which the IRM compound is notadministered.

In some embodiments, the treatment cycle includes five days in which theIRM compound is administered and two days in which the IRM compound isnot administered.

In some embodiments, the treatment of BCC includes at least sixtreatment cycles.

Various other features and advantages of the invention should becomereadily apparent with reference to the following detailed description,examples, claims and appended drawings. In several places throughout thespecification, guidance is provided through lists of examples. In eachinstance, the recited list serves only as a representative group andshould not be interpreted as an exclusive list.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph summarizing data that demonstrate the efficacy ofone embodiment of the method of the invention.

FIG. 2 is a bar graph summarizing data that demonstrate the efficacy ofone embodiment of the method of the invention.

FIG. 3 is a bar graph summarizing data related to the frequency ofadverse local skin reactions.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

Immune response modifiers (“IRMs”) include compounds that possess potentimmunomodulating activity such as, for example, antiviral and antitumoractivity. Certain IRMs modulate the production and secretion ofcytokines. For example, certain IRM compounds induce the production andsecretion of cytokines such as, e.g., Type I interferons, TNF-α, IL-1,IL-6, IL-8, IL-10, IL-12, MIP-1, and/or MCP-1. As another example,certain IRM compounds can inhibit production and secretion of certainT_(H)2 cytokines, such as IL-4 and IL-5. Additionally, some IRMcompounds are said to suppress IL-1 and TNF (U.S. Pat. No. 6,518,265).

Certain IRMs are small organic molecules (e.g., molecular weight underabout 1000 Daltons, preferably under about 500 Daltons, as opposed tolarge biological molecules such as proteins, peptides, and the like)such as those disclosed in, for example, U.S. Pat. Nos. 4,689,338;4,929,624; 4,988,815; 5,037,986; 5,175,296; 5,238,944; 5,266,575;5,268,376; 5,346,905; 5,352,784; 5,367,076; 5,389,640; 5,395,937;5,446,153; 5,482,936; 5,693,811; 5,741,908; 5,756,747; 5,939,090;6,039,969; 6,083,505; 6,110,929; 6,194,425; 6,245,776; 6,331,539;6,376,669; 6,451,810; 6,525,064; 6,541,485; 6,545,016; 6,545,017;6,558,951; 6,573,273; 6,656,938; 6,660,735; 6,660,747; 6,664,260;6,664,264; 6,664,265; 6,667,312; 6,670,372; 6,677,347; 6,677,348;6,677,349; 6,683,088; European Patent 0 394 026; U.S. Patent ApplicationPublication Nos. 2002/0016332; 2002/0055517; 2002/0110840; 2003/0133913;2003/0199538; and 2004/0014779; and International Patent PublicationNos. WO 01/74343; WO 02/46749 WO 02/102377; WO 03/020889; WO 03/043572;WO 03/045391; and WO 03/103584.

Additional examples of small molecule IRMs include certain purinederivatives (such as those described in U.S. Pat. Nos. 6,376,501, and6,028,076), certain imidazoquinoline amide derivatives (such as thosedescribed in U.S. Pat. No. 6,069,149), certain imidazopyridinederivatives (such as those described in U.S. Pat. No. 6,518,265),certain benzimidazole derivatives (such as those described in U.S. Pat.No. 6,387,938), certain derivatives of a 4-aminopyrimidine fused to afive membered nitrogen containing heterocyclic ring (such as adeninederivatives described in U.S. Pat. Nos. 6,376,501; 6,028,076 and6,329,381; and in WO 02/08595), and certain3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine derivatives (such as thosedescribed in U.S. Patent Application Publication No. 2003/0199461).

Other IRMs include large biological molecules such as oligonucleotidesequences. Some IRM oligonucleotide sequences contain cytosine-guaninedinucleotides (CpG) and are described, for example, in U.S. Pat. Nos.6,194,388; 6,207,646; 6,239,116; 6,339,068; and 6,406,705. SomeCpG-containing oligonucleotides can include synthetic immunomodulatorystructural motifs such as those described, for example, in U.S. Pat.Nos. 6,426,334 and 6,476,000. Other IRM nucleotide sequences lack CpGsequences and are described, for example, in International PatentPublication No. WO 00/75304.

Other IRMs include biological molecules such as aminoalkyl glucosaminidephosphates (AGPs) and are described, for example, in U.S. Pat. Nos.6,113,918; 6,303,347; 6,525,028; and 6,649,172.

By stimulating certain aspects of the immune system, as well assuppressing other aspects (see, e.g., U.S. Pat. Nos. 6,039,969 and6,200,592), certain IRMs may be used to treat many diseases andconditions. For example, some IRMs may be useful for treating viraldiseases, neoplasias, fungal diseases, neoplastic diseases, parasiticdiseases, atopic diseases, and opportunistic infections and tumors thatoccur after suppression of cell-mediated immunity. Certain IRMs may beuseful for promoting healing of wounds and post-surgical scars.

Certain formulations of imiquimod, as small molecule IRM compound, havebeen shown to be useful for the therapeutic treatment of certaincancerous or pre-cancerous lesions (See, e.g., Marks et al., J. Am.Acad. Dermatol., 44(5):807-813 (2001); Geisse et al., J. Am. Acad.Dermatol., 47(3): 390-398 (2002); Shumack et al., Arch. Dermatol., 138:1163-1171 (2002); and U.S. Patent Application Publication No.2003/0199538).

The present invention provides a method of treating basal cell carcinomausing IRMs generally and imiquimod in particular. Generally, the methodincludes applying an amount of an IRM compound effective for treatingbasal cell carcinoma, wherein the IRM compound is administered in atreatment cycle that includes at least two consecutive days in which theIRM compound is administered and at least one day in which the IRMcompound is not administered.

The particular embodiment of the invention selected for treating basalcell carcinoma can depend, at least in part, on factors relating to thetumor, the patient, or both. Tumor-related variables may include, forexample, type, size, shape, histological character, growth character,location, and the like. For example, variables may include whether thetumor is primary or recurrent; greater than a particular size; itsduration, growth rate, or both; whether the tumor has indistinctmargins, an aggressive histological pattern, or both; and certainanatomic locations. High risk histological patterns includeinfiltrative/desmoplastic, severe squamous metaplasia, and basosquamous.High-risk locations may include the nose, eyelids, ears, medial canthus,nasolabial fold, scalp, lip, fingers, toes, and genitals.Patient-related variables may include age, medical status, psychologicalfactors, and concomitant medications. For example, patients who areimmunocompromised may be at greater risk because their tumors may bemore likely to demonstrate very aggressive behavior.

Any suitable IRM compound may be used to practice of the invention. Insome embodiments, suitable IRM compounds include but are not limited tothe small molecule IRM compounds described above. Suitable smallmolecule IRM compounds, having a 2-aminopyridine fused to a fivemembered nitrogen-containing heterocyclic ring, include but are notlimited to imidazoquinoline amines such as, for example, amidesubstituted imidazoquinoline amines, sulfonamide substitutedimidazoquinoline amines, urea substituted imidazoquinoline amines, arylether substituted imidazoquinoline amines, heterocyclic ethersubstituted imidazoquinoline amines, amido ether substitutedimidazoquinoline amines, sulfonamido ether substituted imidazoquinolineamines, urea substituted imidazoquinoline ethers, thioether substitutedimidazoquinoline amines, and 6-, 7-, 8-, or 9-aryl or heteroarylsubstituted imidazoquinoline amines; tetrahydroimidazoquinoline aminesincluding, but not limited to, amide substitutedtetrahydroimidazoquinoline amines, sulfonamide substitutedtetrahydroimidazoquinoline amines, urea substitutedtetrahydroimidazoquinoline amines, aryl ether substitutedtetrahydroimidazoquinoline amines, heterocyclic ether substitutedtetrahydroimidazoquinoline amines, amido ether substitutedtetrahydroimidazoquinoline amines, sulfonamido ether substitutedtetrahydroimidazoquinoline amines, urea substitutedtetrahydroimidazoquinoline ethers, and thioether substitutedtetrahydroimidazoquinoline amines; imidazopyridine amines including, butnot limited to, amide substituted imidazopyridine amines, sulfonamidosubstituted imidazopyridine amines, urea substituted imidazopyridineamines, aryl ether substituted imidazopyridine amines, heterocyclicether substituted imidazopyridine amines, amido ether substitutedimidazopyridine amines, sulfonamido ether substituted imidazopyridineamines, urea substituted imidazopyridine ethers, and thioethersubstituted imidazopyridine amines; 1,2-bridged imidazoquinoline amines;6,7-fused cycloalkylimidazopyridine amines; imidazonaphthyridine amines;tetrahydroimidazonaphthyridine amines; oxazoloquinoline amines;thiazoloquinoline amines; oxazolopyridine amines; thiazolopyridineamines; oxazolonaphthyridine amines; thiazolonaphthyridine amines; and1H-imidazo dimers fused to pyridine amines, quinoline amines,tetrahydroquinoline amines, naphthyridine amines, ortetrahydronaphthyridine amines.

In certain embodiments, the IRM compound is an imidazoquinoline aminesuch as, for example,1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.

The IRM compound may be provided in a formulation suitable for topicaladministration. Suitable types of formulations are described, forexample, in U.S. Patent Application Publication No. 2003/0199538. TheIRM compound may be provided in any suitable form including but notlimited to a solution, a suspension, an emulsion, or any form ofmixture. The ERM may be delivered in formulation with anypharmaceutically acceptable excipient, carrier, or vehicle. Theformulation may be delivered in any conventional dosage form includingbut not limited to a cream, an ointment, an aerosol formulation, anon-aerosol spray, a gel, a lotion, a tablet, a lozenge, an elixir, andthe like. The formulation may further include one or more additivesincluding but not limited to adjuvants, skin penetration enhancers,colorants, fragrances, moisturizers, thickeners, and the like.

The composition of a formulation suitable for practicing the inventionwill vary according to factors known in the art including but notlimited to the physical and chemical nature of the IRM compound, thenature of the carrier, the intended dosing regimen, the state of thesubject's immune system (e.g., suppressed, compromised, stimulated), themethod of administering the IRM compound, and the species to which theformulation is being administered. Accordingly, it is not practical toset forth generally the composition of a formulation effective fortreating BCC for all possible applications. Those of ordinary skill inthe art, however, can readily determine an appropriate formulation withdue consideration of such factors.

In some embodiments, the invention includes administering the IRMcompound to a subject in a formulation of, for example, from about0.001% to about 10% (unless otherwise indicated, all percentagesprovided herein are weight/weight with respect to the total formulation)to the subject, although in some embodiments, a suitable formulation mayinclude a concentration of IRM compound that is outside of this range.In certain embodiments, the method includes administering to a subject aformulation that includes from about 0.01% to about 5% IRM compound, forexample, a formulation that includes about 5% IRM compound.

An amount of IRM compound effective for treating basal cell carcinoma(BCC) is an amount sufficient to reduce the size or number of BCClesions, limit or slow the growth of BCC lesions, or both. The preciseamount of IRM compound effective for treating BCC will vary according tofactors known in the art including, but not limited to, the physical andchemical nature of the particular IRM compound being administered; thephysical and chemical nature of the formulation; the size, location, andhistological type of BCC being treated; the intended dosing regimen; thestate of the subject's immune system (e.g., suppressed, compromised,stimulated); and the method of administering the IRM. Accordingly it isnot practical to set forth generally the amount that constitutes anamount of IRM compound effective for treating BCC for all possibleapplications. Those of ordinary skill in the art, however, can readilydetermine the appropriate amount with due consideration of such factors.

In some embodiments, the invention includes administering sufficient IRMcompound to provide a dose of the IRM compound of, for example, fromabout 0.001 mg/cm² to about 100 mg/cm² to the subject, although in someembodiments the methods may be performed by administering the IRMcompound in amounts outside this range. In some of these embodiments,the method includes administering sufficient IRM compound to provide adose of IRM compound of from about 0.1 mg/cm² to about 5 mg/cm² to thesubject, for example, a dose of IRM compound of about 0.5 mg/cm² toabout 2 mg/cm².

The dosing regimen may depend at least in part on many factors known inthe art including but not limited to the physical and chemical nature ofthe IRM compound being administered; the physical and chemical nature ofthe formulation; the size, location, and histological type of the BCCbeing treated; the amount of IRM compound being administered; the stateof the subject's immune system (e.g., suppressed, compromised,stimulated); and the method of administering the IRM compound.Accordingly, it is not practical to set forth generally the dosingregimen effective for treating basal cell carcinoma for all possibleapplications. Those of ordinary skill in the art, however, can readilydetermine an appropriate dosing regimen with due consideration of suchfactors.

An IRM compound can be effective for treating basal cell carcinoma witha treatment regimen that includes administering the IRM compound fromabout once per week to multiple daily doses (e.g., two doses per day).In certain embodiments of the invention, treatment of BCC includesadministering the IRM compound according to a treatment cycle thatincludes at least two consecutive days in which the IRM compound isadministered and at least one day in which the IRM compound is notadministered.

As used herein, a treatment cycle is a repeated cyclical pattern ofscheduled treatment. A treatment period typically includes a schedulednumber of repeated treatment cycles. A treatment cycle may call for aspecified number and schedule of days in which treatment is administered(treatment days) as well as a specified number and schedule of days inwhich no treatment is administered (off days). Thus, a treatment cyclespecifically excludes instances in which scheduled treatments aretemporarily interrupted and then subsequently resumed, for example, toallow one or more adverse reactions to subside. The schedule may be asspecific as necessary for effective treatment. For example, in oneembodiment, a treatment cycle includes five consecutive treatment daysand two consecutive off days per week. In other embodiments, however, atreatment cycle may specify the number of treatment days per week (e.g.,five) and the number of off days per week (e.g., two), but not specifywhen the off days must occur relative to the treatment days.

A treatment cycle that includes at least two consecutive treatment daysand at least one off day can reduce the likelihood and extent of adversereactions to the treatment, thereby minimizing the likelihood thattreatment will be interrupted for one or more rest periods. A treatmentcycle that avoids interrupting treatment can increase the likelihoodthat the treatment can be completed as initially scheduled. Suchtreatment cycles also can provide treatment that is nearly as, equally,or even more effective than treatment cycles requiring more frequentadministration or greater total dosages.

In certain embodiments, the treatment cycle includes five days ofadministering the IRM compound and two days in which the IRM compound isnot administered. In one particular embodiment, the treatment cycleincludes five consecutive days of administering the ERM compound and twoconsecutive days of not administering the IRM compound. This treatmentcycle can provide efficacy equal to or better than, and reduced adversereactions compared to, treatment cycles that call for administering thesame formulation of the IRM compound more frequently or for a greaternumber of doses within a seven-day cycle.

Treatment periods can range from about two weeks to about 24 weeks. Insome embodiments, the treatment period may be a predetermined fixedlength of time. For example, the treatment period can be at least abouttwo weeks, at least about four weeks, at least about six weeks, at leastabout eight weeks, at least about 12 weeks, or at least about 16 weeks,although in some embodiments the methods may be performed byadministering the IRM compound for treatment periods outside this range.Alternatively, the treatment period may terminate upon reaching aparticular milestone. For example, a treatment period of one embodimentof the method according to the present invention may continue until alesion being treated is resolved. Evidence that the lesion is resolvedmay be obtained by any medically acceptable means including but notlimited to clinical examination or histological examination.

FIG. 1 summarizes data regarding one measure of efficacy for oneembodiment of the invention. Subjects were divided into four treatmentgroups: (1) placebo cream, once per day, five days per week (Vehicle5×/week); (2) placebo cream, once per day, seven days per week (Vehicle7×/week); (3) 5% IRM (imiquimod) cream, once per day for five days perweek and two consecutive days without treatment per week (IRM 5×/week);and (4) 5% IRM (imiquimod) cream, once per day, seven days per week (IRM7×/week).

Subjects received treatment for six weeks, then returned twelve weeksafter the end of treatment for a post-treatment visit. At thepost-treatment visit, the entire tumor area—including an area up to a3-4 mm around the pre-treatment tumor margin—was excised. The excisedtissue was examined histologically for evidence of BCC. The proportionof subjects who had no histological evidence of BCC in thepost-treatment excision taken from the treatment site twelve weeks afterthe end of treatment were considered complete histological responders.FIG. 1 shows the proportion of complete histological responders in eachtreatment group. The IRM 5×/week group exhibited the highest proportionof complete histological responders.

FIG. 2 summarizes data regarding a second measure of efficacy for theembodiment of the invention described above. FIG. 2 shows the proportionof composite complete responders in each treatment group. Compositecomplete responders are those who display both (1) no histologicalevidence of BCC twelve weeks after the end of treatment, and (2) noclinical evidence of BCC twelve weeks after the end of treatment. TheIRM 5×/week treatment group exhibited the highest proportion ofcomposite complete responders.

FIG. 3 summarizes a comparison of moderate and severe adverse local skinreactions among the treatment groups (the Vehicle group in FIG. 3 equalsthe combination of the Vehicle 5×/week group and Vehicle 7×/week group).Subjects completed interval visits 1, 3, and 6 weeks after treatment wasinitiated and at twelve weeks after the end of treatment. The presenceof local skin reactions (i.e., erythema, erosion, ulceration, andscabbing) was assessed at each interval visit and at the 12-weekspost-treatment visit on a four-point scale (0, none; 1, mild; 2,moderate; and 3 severe). Reports of local skin reactions are summarizedin FIG. 3, expressed as the percentage of subjects in each treatmentgroup that reported a moderate or sever local skin reaction at any timeduring the study. The incidence of moderate and severe local skinreactions was less in the IRM 5×/week treatment group than in the IRM7×/week treatment group for each local skin reaction shown in FIG. 3.

In some embodiments, administering the IRM compound involves topicalapplication of a formulation that contains IRM compound. The formulationmay be topically applied to a treatment area located on the skin of thesubject. The treatment area can include an area of the skin thatincludes a BCC lesion. The treatment area also may, in some embodiments,include an area of skin surrounding the BCC lesion (i.e., extramarginalskin—skin beyond the margin of the lesion). The treatment area mayinclude extramarginal skin that is uniform or irregular in shape, andmay be of uniform or irregular width around the margin of the lesion. Insome embodiments, the method includes application of a formulation thatincludes an IRM compound to a treatment area that includes a BCC lesionand skin from about 0.5 cm to about 5.0 cm beyond the margin of thelesion, for example, 1.0 cm beyond the margin of the lesion.

The IRM compound may be left on the treatment area for any suitableamount of time. The precise duration of time that a particularapplication of the IRM compound should remain on the treatment site mayvary according to, for example, the dose of the IRM compound beingadministered, the state of the subject's immune system, the size andcharacter of the tumor, the extent to which the subject has experiencedan adverse reaction, and the like. In some embodiments, the methodincludes ensuring that the IRM compound is applied to the treatment sitefor from about one hour to about 48 hours, although certain embodimentsof the invention may be practiced by administering IRM compound to asubject for periods outside this range. In certain embodiments, the IRMcompound is applied for from about two hours to about 24 hours. In otherembodiments, the IRM compound is applied for from about six hours toabout twelve hours, for example, about eight hours.

EXAMPLES

The following examples have been selected merely to further illustratefeatures, advantages, and other details of the invention. It is to beexpressly understood, however, that while the examples serve thispurpose, the particular materials and amounts used as well as otherconditions and details are not to be construed in a matter that wouldunduly limit the scope of this invention.

The IRM compound was provided in a 5% cream in a formulation shown inTable 1, on a percentage weight-by-weight basis. The IRM compound usedto prepare the formulation was imiquimod,1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. Imiquimod andmethods of synthesizing imiquimod are disclosed in, for example, U.S.Pat. No. 4,689,338.

TABLE 1 Formulation Components (% w/w) IRM 5.0 Isostearic Acid 25.0Benzyl Alcohol 2.0 Cetyl Alcohol 2.2 Stearyl Alcohol 3.1 WhitePetrolatum 3.0 Polysorbate 60 3.4 Sorbitan Monostearate 0.6 Glycerin 2.0Methyl Paraben 0.2 Propyl Paraben 0.02 Water 52.98 Xanthan Gum 0.5The formulation was prepared according to the methods described in U.S.Pat. No. 5,238,944. The final formulation had a pH of 5.1, and aviscosity (cps) of 0.33×10⁵.

Example 1

Volunteer subjects with superficial basal cell carcinoma were randomizedto either the 5% imiquimod cream formulation described above or aplacebo cream (Vehicle) in one of two treatment regimens: (1) once dailyfor seven days per week (7×/week), and (2) once daily for fiveconsecutive days per week and no treatment for the remaining two days(5×/week). Subjects in each groups received treatment for six weeks.

Subjects were instructed to administer a single application of cream(Vehicle or 5% imiquimod, as assigned) to a target tumor just prior tonormal sleeping hours according to the dosing regimen to which they wereassigned. The subjects were instructed to wash the tumor lesion prior toapplying the cream, and then rub the cream into the tumor and intoextramarginal skin about 1 cm around the tumor. The subjects wereinstructed to leave the cream in place for at least eight hours withoutocclusion.

Subjects completed interval visits 1, 3, and 6 weeks after treatment wasinitiated and at twelve weeks after the end of treatment. At the12-weeks post-treatment visit, the treatment area was clinicallyevaluated and the entire tumor area—an area up to a 3-4 mm around thepre-treatment tumor margin—was excised. The excised tissue was examinedhistologically for evidence of BCC. FIG. 1 summarizes the results of thehistological assessment, expressed as the percentage of subjects in eachtreatment group that exhibited a complete histological response, i.e.,the proportion of subjects who had no histological evidence of BCC inthe post-treatment excision taken from the treatment site twelve weeksafter the end of treatment. FIG. 2 summarizes the results of thecomposite assessment, expressed as the percentage of subjects havingboth (a) no clinical evidence of BCC twelve weeks after the end oftreatment, and (b) a complete histological response.

The presence of local skin reactions (i.e., erythema, erosion,ulceration, and scabbing) was assessed at each interval visit and at the12-weeks post-treatment visit. Reports of local skin reactions aresummarized in FIG. 3, expressed as the percentage of subjects in eachtreatment group that reported a given local skin reaction during thestudy.

The complete disclosures of the patents, patent documents andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. In case of conflict,the present specification, including definitions, shall control.

Various modifications and alterations to this invention will becomeapparent to those skilled in the art without departing from the scopeand spirit of this invention. Illustrative embodiments and examples areprovided as examples only and are not intended to limit the scope of theinvention. The scope of the invention is limited only by the claims setforth as follows.

1. A method of treating a patient diagnosed with superficial basal cellcarcinoma for six weeks, the method comprising: applying an effectiveamount of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine(imiquimod) to a treatment area of the patient in accordance with asix-week treatment cycle for treating superficial basal cell carcinoma;wherein, the treatment area comprises a biopsy-confirmed superficialbasal cell carcinoma lesion and about one centimeter of extramarginalskin that surrounds and extends beyond the lesion; wherein, the six-weektreatment cycle comprises applying the imiquimod to the treatment areain accordance with a seven-day treatment regimen for six consecutiveweeks; wherein, the seven-day treatment regimen comprises (a) applyingthe imiquimod to the treatment area once per day prior to sleeping hoursfor five consecutive days and (b) not applying the imiquimod to thetreatment area for two consecutive days; and wherein, the imiquimod,once applied to the treatment area, is left on the treatment area forabout 8 hours.
 2. The method of claim 1, wherein the treatment area islocated on the head.
 3. The method of claim 1, wherein the treatmentarea is located on the neck.
 4. The method of claim 1, wherein thetreatment area is selected from the group consisting of the nose,eyelids, ears, medial canthus, nasolabial fold, scalp, lip, fingers,toes, genitals and sun exposed areas.
 5. The method of claim 1, whereinthe method further includes the step of: conducting a first follow-upvisit at approximately 12 weeks post-treatment to assess the treatmentsite for clinical clearance.
 6. The method of claim 5, wherein themethod further includes the step of: excising the treatment area forhistological evidence of superficial basal cell carcinoma.
 7. The methodof claim 1, further comprising assessing patient response to thesix-week treatment cycle after the end of the six-week treatment cycle,wherein the six-week treatment cycle (a) is about at least as effectiveas other treatments with 5% imiquimod cream that require more frequentadministrations or greater total dosages, and (b) provides a reducedincidence of treatment interruptions for one or more rest periods due toadverse reactions.
 8. The method of claim 1, further comprisingassessing patient response to the six-week treatment cycle after the endof the six-week treatment cycle, by measuring: a complete histologicalresponse of the patient; a composite complete response of the patient;or a local skin reaction rate of the patient; wherein a completehistological response rate of about 82% is achieved at about 12 weeksafter the six-week treatment cycle, a composite complete response rateof about 75% is achieved at about 12 weeks after the six-week treatmentcycle, or a local skin reaction rate is achieved as follows at about 12weeks after the six-week treatment cycle: an erythema local skinreaction rate of about 88%; an erosion local skin reaction of about 36%;an ulceration local skin reaction of about 22%; or a scabbing local skinreaction of about 52%.
 9. The method of claim 1, wherein the effectiveamount of imiquimod is about 0.001 mg/cm2 to about 100 mg/cm².
 10. Themethod of claim 1, wherein the effective amount of imiquimod is about0.1 mg/cm2 to about 5 mg/cm².
 11. The method of claim 1, wherein theeffective amount of imiquimod is about 0.5 mg/cm2 to about 2 mg/cm². 12.The method of claim 1, wherein the effective amount of imiquimod iseffective to reduce the size of the lesion.
 13. The method of claim 1,wherein the effective amount of imiquimod is effective to limit thegrowth of the lesion.
 14. The method of claim 1, wherein the effectiveamount of imiquimod is effective to slow the growth of the lesion. 15.The method of claim 1, wherein the effective amount of imiquimod iseffective to reduce the number of lesions.
 16. The method of anyone ofclaims 1-15, wherein said application step comprises: applying theimiquimod as an imiquimod cream to the treatment area, wherein theimiquimod cream contains imiquimod in an amount of about 5%.
 17. Themethod of anyone of claims 1-15, wherein the imiquimod is a 5% imiquimodcream.
 18. A method of treating a patient diagnosed with superficialbasal cell carcinoma for six weeks, the method comprising: applying aneffective amount of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine(imiquimod) to a treatment area of the patient in accordance with asix-week treatment cycle for treating superficial basal cell carcinoma;wherein, the treatment area comprises a biopsy-confirmed superficialbasal cell carcinoma lesion and about one centimeter of extramarginalskin that surrounds and extends beyond the lesion; wherein, the six-weektreatment cycle comprises applying the imiquimod to the treatment areain accordance with a seven-day treatment regimen for six consecutiveweeks; wherein, the seven-day treatment regimen comprises (a) applyingthe imiquimod to the treatment area once per day prior to sleeping hoursfor five consecutive days and (b) not applying the imiquimod to thetreatment area for two consecutive days; and wherein, the imiquimod,once applied to the treatment area, is left on the treatment area forabout 8 hours, the method having a response rate for multiple subjectstreated with the method of at least as high a percentage as a responserate for multiple subjects treated with a control method, the controlmethod comprising administering to a subject an identical amount ofimiquimod in a control cycle in which the identical amount of imiquimodis administered to a treatment area of a control patient in accordancewith a six-week control cycle; wherein, the treatment area comprises abiopsy-confirmed superficial basal cell carcinoma lesion and about onecentimeter of extramarginal skin that surrounds and extends beyond thelesion; wherein, the six-week control cycle comprises applying theimiquimod to the treatment area in accordance with a seven-day treatmentregimen for six consecutive weeks; wherein, the seven-day treatmentregimen comprises (a) applying the imiquimod to the treatment area onceper day prior to sleeping hours daily; and wherein, the imiquimod, onceapplied to the treatment area, is left on the treatment area for about 8hours.
 19. The method of claim 18, the treatment method additionallyhaving fewer treatment interruptions for one or more rest periods due toadverse reactions compared to the control method.
 20. The method ofclaim 18, wherein the imiquimod comprises a 5% imiquimod cream.
 21. Themethod of claim 18, wherein the response rate is measured after the endof treatment with the treatment method or the control method as acomplete histological response.
 22. The method of claim 21, wherein thecomplete histological response rate of the treatment method is about 82%at about 12 weeks after the six-week treatment cycle.
 23. The method ofclaim 18, wherein the response rate is measured after the end oftreatment with the treatment method or the control method as a compositeresponse rate assessment of subjects having both (a) an elimination ofclinical evidence of basal cell carcinoma, and (b) a completehistological response.
 24. The method of claim 23, wherein the compositeresponse rate of the treatment method is about 75% at about 12 weeksafter the six-week treatment cycle.
 25. The method of claim 18, whereinthe response rate is measured after the end of treatment with thetreatment method or the control method as a local skin reaction rate.26. The method of claim 25, wherein the local skin reaction rate is atleast as follows at about 12 weeks after the six-week treatment cycle:an erythema local skin reaction rate of 88%; an erosion local skinreaction rate of about 36%; an ulceration local skin reaction rate ofabout 22%; or a scabbing local skin reaction rate of about 52%.